Trialkyl cationic lipids and methods of use thereof

Abstract

The present invention provides compositions and methods for the delivery of therapeutic agents to cells. In particular, these include novel cationic lipids and nucleic acid-lipid particles that provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo. The compositions of the present invention are highly potent, thereby allowing effective knock-down of a specific target protein at relatively low doses. In addition, the compositions and methods of the present invention are less toxic and provide a greater therapeutic index compared to compositions and methods previously known in the art.

What is claimed is: 
     
       1. A cationic lipid having one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       2. A lipid particle comprising a cationic lipid of  claim 1 . 
     
     
       3. The lipid particle of  claim 2 , wherein the particle further comprises a non-cationic lipid. 
     
     
       4. The lipid particle of  claim 3 , wherein the non-cationic lipid is selected from the group consisting of a phospholipid, cholesterol, or a mixture of a phospholipid and cholesterol. 
     
     
       5. The lipid particle of  claim 4 , wherein the phospholipid comprises dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), or a mixture thereof. 
     
     
       6. The lipid particle of  claim 4 , wherein the cholesterol is a cholesterol derivative. 
     
     
       7. The lipid particle of  claim 3 , wherein the particle further comprises a conjugated lipid that inhibits aggregation of particles. 
     
     
       8. The lipid particle of  claim 7 , wherein the conjugated lipid that inhibits aggregation of particles comprises a polyethyleneglycol (PEG)-lipid conjugate. 
     
     
       9. The lipid particle of  claim 8 , wherein the PEG-lipid conjugate comprises a PEG-diacylglycerol (PEG-DAG) conjugate, a PEG-dialkyloxypropyl (PEG-DAA) conjugate, or a mixture thereof. 
     
     
       10. The lipid particle of  claim 7 , wherein the particle further comprises a therapeutic agent. 
     
     
       11. The lipid particle of  claim 10 , wherein the therapeutic agent is a nucleic acid. 
     
     
       12. The lipid particle of  claim 11 , wherein the nucleic acid is an interfering RNA. 
     
     
       13. The lipid particle of  claim 12 , wherein the interfering RNA is selected from the group consisting of a small interfering RNA (siRNA), an asymmetrical interfering RNA (aiRNA), a microRNA (miRNA), a Dicer-substrate dsRNA, a small hairpin RNA (shRNA), and mixtures thereof. 
     
     
       14. The lipid particle of  claim 12 , wherein the interfering RNA is an siRNA. 
     
     
       15. A pharmaceutical composition comprising a lipid particle of  claim 10  and a pharmaceutically acceptable carrier. 
     
     
       16. A method for introducing a therapeutic agent into a cell, the method comprising:
 contacting the cell with a lipid particle of  claim 10 . 
 
     
     
       17. A method for the in vivo delivery of a therapeutic agent, the method comprising:
 administering to a mammal a lipid particle of  claim 10 . 
 
     
     
       18. A method for treating a disease or disorder in a mammal in need thereof, the method comprising:
 administering to the mammal a therapeutically effective amount of a lipid particle of  claim 10 .